Drive mechanism for a drug delivery device

ABSTRACT

The present disclosure concerns a drive mechanism for a drug delivery device, having a first and a second state and comprising a piston rod configured to be moved in a distal direction when the drive mechanism is operated and an adjusting member, wherein the adjusting member is rotatable relative to a body of the drug delivery device in the first state of the drive mechanism and is prevented from rotating relative to the body in the second state of the drive mechanism, and wherein the adjusting member is configured to adjust an axial position of the piston rod in the first state of the drive mechanism.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application pursuant to35 U.S.C. § 371 of International Application No. PCT/EP2014/054532 filedMar. 10, 2014, which claims priority to European Patent Application No.13159054.9 filed Mar. 13, 2013. The entire disclosure contents of theseapplications are herewith incorporated by reference into the presentapplication.

TECHNICAL FIELD

The present invention relates to a drive mechanism for a drug deliverydevice.

BACKGROUND

Drug delivery devices are generally known for the administration of amedicinal product, for example insulin or heparin, but also for othermedicinal products, in particular for self-administration by a patient.A drug delivery device may be configured as a pen-type injector whichmay dispense a pre-set dose of a fluid medicinal product. However, thedrug delivery device may also deliver a variable dose of the medicinalproduct.

Before the first use of the drug delivery device, the user may have todispense a small amount of the product. Thereby, the effect ofmanufacturing tolerances of the mechanical components of the drugdelivery device may be eliminated. The operation of dispensing a smallamount of a product before the first use is also referred to as apriming operation of the drug delivery device. Users who are unfamiliarwith the drug delivery device may fail to or incorrectly prime theirdrug delivery device before dispensing the first dose. Anotherdisadvantage of a drug delivery device requiring a priming operation isthat a user might accidently inject a priming dose. Moreover, primingoperations result in a waste of the medicinal product as the medicinalproduct expelled during the priming operation cannot be used to treatthe patient.

SUMMARY

It is an object of the present disclosure to provide a drive mechanismfor use in a drug delivery device which helps to improve usability andensures the accuracy of the first administered dose of a medicinalproduct.

This object is solved by the drive mechanism according to present claim1.

According to a first aspect of the present disclosure, a drive mechanismfor a drug delivery device is provided. The drive mechanism has a firstand a second state and comprises a piston rod configured to be moved ina distal direction when the drive mechanism is operated and an adjustingmember, wherein the adjusting member is rotatable relative to a body ofthe drug delivery device in the first state of the drive mechanism andis prevented from rotating relative to the body in the second state ofthe drive mechanism and wherein the adjusting member is configured toadjust an axial position of the piston rod in the first state of thedrive mechanism.

The terms “distal” and “proximal” shall be defined as follows. In anassembled drug delivery device, the distal end of the drive mechanism isdefined as the end which is closest to a dispensing end of the drugdelivery device. In an assembled drug delivery device, the proximal endof the drive mechanism is defined as the end which is furthest away fromthe dispensing end of the drug delivery device. Moreover, a distaldirection is defined as a direction towards the distal end and aproximal direction is defined as a direction towards the proximal end.

The drive mechanism may be a mechanism that allows to set a dose and todispense a dose of a medicinal product. The drive mechanism may comprisethe piston rod, the elements that are configured to move the piston rodand elements that are configured to constrain a movement of the pistonrod. The drive mechanism may include all elements that are required tocarry out the dose setting and/or dose dispensing operation.

The first state of the drive mechanism may be a pre-assembled state. Inthe first state, the drive mechanism may be assembled to a cartridgeholder holding a cartridge. However, in the first state, mechanicaltolerances between the drive mechanism and the cartridge holder andmechanical tolerances between the elements of the drive mechanism may bepresent. In the first state, due to manufacturing tolerances or othermechanical tolerances, the drive mechanism may be not correctly alignedto other elements of the drug delivery device. In particular, thedistance between elements of the drive mechanism, for example betweenthe piston rod and a bung of the cartridge, may not be well-defined. Dueto mechanical tolerances and other tolerances in the manufacturingprocess, this distance may vary from one drug delivery device to anotherin the first state of the drive mechanism.

Moreover, other elements of the drug delivery device, e.g. a button, maynot have been assembled to the drug delivery device in the first stateof the drive mechanism.

In the first state, the drive mechanism may be usable for preparativepurposes only and may not be suited for a dose setting operation or adose dispense operation.

The first state may be defined as a state wherein the adjusting memberis rotatable relative to a body of the drug delivery device.

The second state of the drive mechanism may be defined as a statewherein the adjusting member is prevented from rotating relative to thebody.

The drive mechanism being in its first state may be transferred to itssecond state by rotationally locking the adjusting member relative tothe body. Further, the drive mechanism being in its second state may betransferred to its first state by releasing the engagement between theadjusting member and the body such that the adjusting member ispermitted to rotate relative to the body. In some embodiments, theengagement may only be released if one of the adjusting member and thebody is damaged during the release.

In the second state of the drive mechanism, the adjusting member may beengaged to the body such that the adjusting member is permitted torotate relative to the body and such that the engagement of theadjusting member with the body may only be released by damaging at leastone of the elements of the drive mechanism or of the drug deliverydevice. In alternate embodiments, the adjusting member may be releasablyengaged to the body in the second state of the drive mechanism.Accordingly, in these embodiments, the engagement of the adjustingmember with the body may be released without damaging one of theelements of the drive mechanism or of the drug delivery device.

In the second state of the drive mechanism, the tolerances may have beeneliminated. In the second state of the drive mechanism, the drugdelivery device may be used by a patient for the application of amedicinal product. Accordingly, the drive mechanism may be ready tocarry out a dose setting and a dose dispensing operation in the secondstate. In particular, when the drive mechanism is operated for the firsttime in its second state, the drive mechanism can be used without therequirement of a priming step to prepare for the first dose delivery.

The piston rod may be configured to be moved in a distal direction whenthe drive mechanism is operated in the second state of the drivemechanism. The operation of the drive mechanism may be a dose dispenseoperation.

The piston rod may also be configured to be moved in a distal directionwhen the drive mechanism is operated in the first state of the drivemechanism. In this case, the operation of the drive mechanism may be apriming operation.

The adjusting member may comprise a nut. The adjusting member may bethreadedly engaged with the piston rod. The adjusting member mayconstrain a movement of the piston rod in the second state of the drivemechanism. In particular, the adjusting member may constrain a movementof the piston rod in the second state of the drive mechanism such thatthe piston rod is permitted only to carry out a concurrent axial androtational movement relative to the adjusting member. As the adjustingmember is prevented from rotating relative to the body in the secondstate of the drive mechanism, the adjusting member may constrain amovement of the piston rod in the second state of the drive mechanismsuch that the piston rod is permitted only to carry out a concurrentaxial and rotational movement relative to the body.

Further, the adjusting member may be engaged with the piston rod in thefirst state of the drive mechanism as well. In particular, the adjustingmember may be threadedly engaged with the piston rod in the first stateof the drive mechanism. However, as the adjusting member is permitted torotate relative to the body in the first state of the drive mechanism,the adjusting member may not constrain a movement of the piston rodrelative to the body in the first state of the drive mechanism. Instead,the piston rod may be permitted to be moved axially relative to the bodywithout rotating relative to the body, in the first state of the drivemechanism.

In particular, the adjusting member may be configured to be rotatedrelative to the body in the first state of the drive mechanism. Thereby,the adjusting member may move the piston rod axially relative to thebody such that the axial position of the piston rod may be adjusted inthis manner.

Further, the adjusting member may be configured such that a rotation ofan external member is converted into a rotation of the adjusting member.

The external member may not be a part of the drive mechanism. Instead,the external member may be a part of an external assembly machine thatis configured to engage with the adjusting member in the first state ofthe drive mechanism and that is removed from the drug delivery device inthe second state of the drive mechanism. Accordingly, the adjustingmember may be configured to be engaged with the external member in thefirst state of the drive mechanism.

The adjusting member may comprise a controlling feature that is suitablefor being engaged with the external member. The controlling feature maybe integrally formed with the adjusting member. The controlling featuremay comprise teeth arranged at a periphery of the adjusting member. Inparticular, the periphery of the adjusting member may be formed as atoothed gear which is configured to be engaged with the external member.

The external member may also comprise a toothed gear. The externalmember may be driven, in particular rotated, by a drive mechanism of theexternal assembly machine. The external member may rotate the adjustingmember such that the adjusting member moves the piston rod in the distaldirection towards the bung of the cartridge.

Further, the drive mechanism may comprise a rotation preventing memberwherein the rotation preventing member is configured to be engaged withthe adjusting member in the second state of the drive mechanism therebypreventing a rotation of the adjusting member relative to the body.

In particular, the rotation preventing member may be configured to beengaged with the controlling feature of the adjusting member in thesecond state of the drive mechanism. Accordingly, the controllingfeature may fulfill two purposes in the drive mechanism. The controllingfeature may be configured such that a rotation of the external member istransferred to a rotation of the adjusting member, thereby moving thepiston rod in the distal direction, when the controlling feature isengaged with the external member. Further, the controlling feature maybe configured such that a further rotation of the adjusting memberrelative to the body is prevented when the controlling feature isengaged with the rotation preventing member.

Alternatively, the rotation preventing member may be configured toengage with another element of the adjusting member.

The engagement of the rotation preventing member with the adjustingmember in the second state may provide further advantages. The rotationpreventing member may close an opening in the body and in a housing ofthe drug delivery device when engaged with the adjusting member.Thereby, the rotation preventing member may provide for a smooth surfaceof the drug delivery device. The rotation preventing member may preventthe interior of the drug delivery device from being polluted in thesecond state of the drive mechanism as the rotation preventing membercloses the interior of the drug delivery device and thereby forms anencapsulation of the interior.

Further, the adjusting member may comprise a first contact surface and,in the second state of the drive mechanism, the first contact surfacemay abut the body, thereby preventing the adjusting member from rotatingrelative to the body. In particular, the body may comprise a secondcontact surface. In the second state of the drive mechanism, the firstcontact surface may abut the second contact surface.

A rotation of the adjusting member relative to the body may be preventedby a frictional engagement of the first contact surface with the body.Accordingly, the adjusting member may be self-locking. The frictionalengagement may be generated by an axial load transmitted to theadjusting member by the piston rod resulting in friction between thefirst and the second contact surface.

In particular, the first contact surface of the adjusting member and thecorresponding second contact surface of the body may comprise faceswhich are arranged in an angle non-perpendicular to a longitudinal axisof the drive mechanism. When these faces abut each other, an increasedfrictional engagement occurs which prevents rotation of the adjustingmember relative to the body.

Alternatively, the frictional engagement between the first contactsurface of the adjusting member and the body may not be sufficientlystrong to prevent a rotation between the adjusting member and the body.In this case, the frictional engagement impedes a rotation of theadjusting member relative to the body. Accordingly, due to thefrictional engagement, the torque required to rotate the adjustingmember relative to the body may be increased.

Additionally or alternatively, the first contact surface may compriselocking features that are configured to engage with the body when thecontact surface abuts the body in the second state of the drivemechanism, thereby preventing the adjusting member from rotatingrelative to the body.

The locking features may comprise ramp features arranged on the firstand the second contact surface. The locking features may be configuredsuch that they allow a rotation of the adjusting member relative to thebody when the adjusting member has a small amount of axial play relativeto the body. Further, the locking features may be configured to preventa rotation of the adjusting member relative to the body when the smallamount of play is eliminated. Accordingly, in the first state of thedrive mechanism, the locking features may not prevent a rotation of theadjusting member relative to the body. In the second state of the drivemechanism, the axial play between the adjusting member and the body maybe eliminated, e.g. by a rotation preventing member being engaged to theadjusting member, thereby the locking features prevent any furtherrotation of the adjusting member relative to the body.

Further, in the second state of the drive mechanism, a force may beexerted in a proximal direction onto the adjusting member therebybringing the first contact surface in abutment with the body. The forcein the proximal direction may be exerted by the piston rod. The forcemay be generated by an abutment of the piston rod with the bung,resulting in a tension of a system comprising the piston rod and theadjusting member.

Additionally or alternatively, an adhesive may prevent the adjustingmember from rotating relative to the body in the second state of thedrive mechanism. The adhesive may be arranged on the first contactsurface and/or the second contact surface. Accordingly, when the contactsurface abuts the second contact surface, the adhesive couples the firstand the second contact surface with each other. Further, the adhesivemay be additionally activated using ultra-violet light, ultrasonicallyor by using radio frequency energy.

Additionally or alternatively, the adjusting member may be welded to thebody in the second state of the drive mechanism.

Each of welding and adhesive coupling provides a strong joint betweenthe adjusting member and the body. In particular, welding and adhesivecoupling allow providing an adjusting member which does not compriseteeth. Accordingly, the adjusting member can be coupled with the body bythe adhesive or by the welding in any rotational position relative tothe body. In particular, the adjusting member does not have to be movedin one of a number discrete rotational positions relative to the bodydefined by teeth. Accordingly, these embodiments allow for a highresolution in the angular position of the adjusting member. Accordingly,as the adjusting member can be oriented in one of an unlimited number ofrotational positions relative to the body, the axial load applied by thepiston rod to the bung can be set very precisely.

Further, the adjusting member may comprise a fixing feature. The fixingfeature may be either configured to engage with the body of the drugdelivery device such that the adjusting member is moveable in an axialdirection relative to the body only by a small predetermined distance orthe fixing feature may be configured to engage with the body of the drugdelivery device such that the adjusting member is prevented from movingin an axial direction relative to the body.

In particular, the fixing feature may allow the adjusting member to moverelative to the body only by a small predetermined distance in the firststate of the drive mechanism. In the second state of the drivemechanism, the fixing feature may cooperate with the rotation preventingmember such that the adjusting member is prevented from moving axiallyrelative to the body. In particular, the rotation preventing member mayeliminate the axial play such that no axial play between the adjustingmember and the body is present in the second state of the drivemechanism.

The fixing feature may be configured to engage with the body by asnap-fit connection. The body may comprise a protrusion that isconfigured such that the fixing feature may be snap fitted to theprotrusion. The protrusion of the body may be rotationally symmetricthereby permitting the adjusting member to rotate relative to the body.

Further, the present disclosure concerns a drug delivery devicecomprising the drive mechanism and the body wherein the drive mechanismis arranged at least partially inside the body.

In particular, the drive mechanism may be the drive mechanism disclosedabove such that every structural and functional feature disclosed withrespect to that drive mechanism may also be present in the drug deliverydevice.

The body may comprise a first engagement feature that is configured toengage the adjusting member in the second state of the drive mechanism,thereby preventing a rotation of the adjusting member relative to thebody in the second state of the drive mechanism.

The first engagement feature may be arranged at an inner surface of thebody. The first engagement feature may comprise a locking arm. The firstengagement feature may comprise teeth.

Further, the adjusting member may comprise a second engagement featurewherein the first engagement feature of the body may be configured toengage with the second engagement feature of the adjusting member in thesecond state of the drive mechanism.

The second engagement feature may comprise teeth arranged at theperiphery of the adjusting member. In particular, the teeth of the firstengagement feature may be configured to engage with the teeth of thesecond engagement feature in the second state of the drive mechanism.

Alternatively, the second engagement feature may comprise a fragilesurface that is configured to be crushed when the first engagementfeature of the body engages with the second engagement feature. Thefragile surface may be formed by a thin material. The fragile surfacemay form a ring. The fragile surface provides the advantage that itallows the first and the second engagement feature to engage with eachother not only in a limited number of discrete positions but in anyrotational position relative to each other. Thus, the position of theadjusting member may be chosen very precisely without being restrictedto one of a number of discrete positions such that the axial loadapplied to the bung by the piston rod may be set very precisely.

Further, the drug delivery device may comprises a housing, wherein thebody is arranged inside the housing, wherein the body has a first and asecond rotational position relative to the housing, and wherein thefirst engagement feature of the body is engaged with the adjustingmember when the body is in its second rotational position.

Accordingly, the body may be rotatable relative to the housing.

In particular, the housing may comprise a non-circular inner diameter.Ramp features may be arranged at the inner surface of the housing. Thebody may also comprise a non-circular outer diameter. The firstrotational position of the body relative to the housing is configuredsuch that the first engagement feature of the body is arranged in adistance relative to the second engagement feature of the adjustingmember. The second rotational position may be configured such that thefirst engagement feature is engaged with the second engagement feature.In particular, during the rotation of the body relative to the housing,the ramp features of the housing may move the first engagement featureinto engagement with the second engagement feature.

Further, the body may comprise an opening arranged at a periphery of thebody, wherein an external member and/or a rotation-preventing member ofthe drive mechanism are each moveable at least partially through theopening into the body, thereby engaging with the adjusting member.

The opening may form a slot. The opening may be closed by a rotationpreventing member or by another member in the second state of the drivemechanism.

Another aspect of the present disclosure concerns a method of assemblingthe drive mechanism. The method comprises the steps of:

-   -   providing the drive mechanism in its first state,    -   rotating the adjusting member relative to the body of the drug        delivery device, thereby adjusting the axial position of the        piston rod, and    -   rotationally locking the adjusting member to the body such that        the adjusting member is prevented from rotating relative to the        body, thereby transferring the drive mechanism to its second        state.

In particular, the drive mechanism may be the drive mechanism disclosedabove such that every structural and functional feature disclosed withrespect to that drive mechanism may also be present in the method.

The term “medicinal product”, as used herein, preferably means apharmaceutical formulation containing at least one pharmaceuticallyactive compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a protein, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(w-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

-   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   des Pro36 Exendin-4(1-39),-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),    wherein the group -Lys6-NH2 may be bound to the C-terminus of the    Exendin-4 derivative;    or an Exendin-4 derivative of the sequence-   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),-   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,-   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]    Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(S1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2;    or a pharmaceutically acceptable salt or solvate of any one of the    afore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, β, ε, δ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and 6 approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (C_(H)) and the variable region (V_(H)). Inone species, the constant region is essentially identical in allantibodies of the same isotype, but differs in antibodies of differentisotypes. Heavy chains γ, α and δ have a constant region composed ofthree tandem Ig domains, and a hinge region for added flexibility; heavychains μ and ε have a constant region composed of four immunoglobulindomains. The variable region of the heavy chain differs in antibodiesproduced by different B cells, but is the same for all antibodiesproduced by a single B cell or B cell clone. The variable region of eachheavy chain is approximately 110 amino acids long and is composed of asingle Ig domain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H—H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

In the following, the disclosed devices and methods are described infurther detail with reference to the drawings, wherein

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a part of a drug delivery device in a cross-sectional view,

FIG. 2 shows an adjusting member being engaged with a body,

FIG. 3 shows the adjusting member shown in FIG. 2 in a perspective view,

FIG. 4 shows an engagement of an external member with the drug deliverydevice shown in FIG. 1,

FIG. 5 shows a part of the drug delivery device shown in FIG. 1 in aperspective view with some of the elements of the drug delivery deviceshown partially transparent,

FIG. 6 shows a cross-sectional view of a drive mechanism in its secondstate,

FIG. 7 shows the adjusting member being engaged with the body accordingto a second embodiment of the drive mechanism,

FIG. 8 shows the adjusting member according to a third embodiment of thedrive mechanism,

FIG. 9 shows the adjusting member being engaged with the body accordingto a fourth embodiment of the drive mechanism,

FIG. 10 shows the drive mechanism according to a fifth embodiment of thedrive mechanism,

FIG. 11 shows a rotation preventing member approaching the drivemechanism according to a sixth embodiment of the drive mechanism in thefirst state of the drive mechanism,

FIG. 12 shows a cross-sectional view of an engagement of the rotationpreventing member shown in FIG. 11 with the adjusting member accordingto the sixth embodiment of the drive mechanism,

FIG. 13 shows a perspective view of an engagement of the rotationpreventing member shown FIGS. 11 and 12 with the adjusting memberaccording to the sixth embodiment of the drive mechanism,

FIG. 14 shows the drive mechanism according to a seventh embodiment,

FIG. 15 shows the drive mechanism shown in FIG. 14 in its first state,

FIG. 16 shows the drive mechanism shown in FIG. 14 in its second state,

FIG. 17 shows the drive mechanism according to the seventh embodimentwhen an alternative assembly tool is used,

FIG. 18 shows the drug delivery device with the drive mechanismaccording to an eighth embodiment in a first stage of the assemblyprocess,

FIG. 19 shows a second stage of the assembly process of the drugdelivery device with the drive mechanism according to the eighthembodiment,

FIG. 20 shows a third stage of the assembly process of the drug deliverydevice with the drive mechanism according to the eighth embodiment,

FIG. 21 shows the body according to the ninth embodiment of the drivemechanism,

FIG. 22 shows a perspective view of the adjusting member according tothe ninth embodiment of the drive mechanism,

FIG. 23 shows a perspective view of the drug delivery device accordingto the ninth embodiment in the first state of the drive mechanism,

FIG. 24 shows a cross-sectional view of the drug delivery deviceaccording to the ninth embodiment in the first state of the drivemechanism,

FIG. 25 shows a perspective view of the drug delivery device accordingto the ninth embodiment in the second state of the drive mechanism,

FIG. 26 shows a cross-sectional view of the drug delivery deviceaccording to the ninth embodiment in the second state of the drivemechanism,

FIG. 27 shows the adjusting member according to a tenth embodiment in aperspective view, and

FIG. 28 shows a cross-sectional view of the drug delivery deviceaccording to the tenth embodiment in the second state of the drivemechanism.

DETAILED DESCRIPTION

FIG. 1 shows a part of a drug delivery device 1 in a cross-sectionalview. The drug delivery device 1 shown in FIG. 1 is an injection device.In particular, the drug delivery device 1 is a pen-type injectiondevice. Moreover, the drug delivery device 1 is a fixed dose device. Thedrug delivery device 1 is a disposable device.

The drug delivery device 1 comprises a drive mechanism 2. The drivemechanism 2 comprises a piston rod 3. The piston rod 3 is movable in thedistal direction 4. In particular, the piston rod 3 is configured to bemoved in the distal direction 4 in a dose dispense operation.

Further, the drug delivery device 1 comprises a cartridge holder 5. Acartridge 6 comprising a bung 7 is arranged in the cartridge holder 5.By a movement of the bung 7 in a distal direction 4 towards an outlet ofthe cartridge 6, a medicinal product may be expelled from the cartridge6.

Moreover, the drug delivery device comprises a body 10. In particular,the body 10 is an inner body. Further, the drug delivery devicecomprises a housing 11. The body 10 is arranged inside the housing 11.The body 10 is fixed to the housing 11 such that it cannot move relativeto the housing 11. Further, the cartridge holder 5 comprising thecartridge 6 is fixed to the body 10. The drive mechanism 2 is arrangedat least partially inside the body 10.

The drive mechanism 2 has a first state and a second state. In the firststate, the distance between the piston rod 3 and the bung 7 is notwell-defined. For example, manufacturing tolerances and other mechanicaltolerances may be present in the first state. Accordingly, the distancebetween the bung 7 and the distal end of the piston rod 3 may vary fromone drug delivery device 1 to another in the first state. FIG. 1 showsthe drive mechanism 2 in its first state.

As will be discussed later, in the second state of the drive mechanism2, the distance between the bung 7 and the piston rod 3 is well-defined.In particular, the piston rod 3 may abut the bung 7 in the second stateof the drive mechanism 2.

The piston rod 3 comprises a bearing 8. The bearing 8 is arranged at thedistal end of the piston rod 3. The bearing 8 is integrally formed withthe piston rod 3. Alternatively, the bearing 8 may be snap-fitted to amain body of the piston rod 3. The bearing 8 is configured to exert aforce on the bung 7 when the piston rod 3 is moved in the distaldirection.

Moreover, the drive mechanism 2 comprises a drive member (not shown inFIG. 1) which is configured to control a movement of the piston rod 3.The drive member may comprise a drive sleeve (not shown in FIG. 1).

Further, the drive mechanism 2 comprises an adjusting member 9. In thefirst state of the drive mechanism 2, the adjusting member 9 isrotatable relative the body 10 of the drug delivery device 1. In thefirst state, a rotational movement of the adjusting member 9 may adjustthe axial position of the piston rod 3 relative to the adjusting member9 and, thereby, relative to the body 10. However, in the second state ofthe drive mechanism 2, the adjusting member 9 is prevented from therotating relative to the body 10. In the second state of the drivemechanism 2, the adjusting member 9 constrains a movement of the pistonrod 3 relative to the body 10.

FIG. 2 shows the adjusting member 9 being engaged with the body 10. FIG.3 shows the adjusting member 9 in a perspective view.

The adjusting member 9 comprises a nut.

The adjusting member 9 is engaged to the body 10 in the first and in thesecond state of the drive mechanism 2. The adjusting member 9 comprisesa fixing feature 12 that is engaged with the body 10 of the drugdelivery device 1 in the first and in the second state of the drivemechanism 2. The fixing feature 12 is configured such that the adjustingmember 9 is either not movable axially relative to the body 10 or thatthe adjusting member 9 is moveable only by a small predetermineddistance when the adjusting member 9 is engaged to the body 10.

The fixing feature 12 is configured to be snap-fitted to the body. Thebody 10 comprises a corresponding protrusion 13 such that the fixingfeature 12 is configured to be snap-fitted to the protrusion 13. Theprotrusion 13 is formed as a rotary bearing.

The fixing feature 12 is configured such that the adjusting member 9 hasa small amount of play for an axial movement when engaged with the body10. This small amount corresponds to the small predetermined distance bywhich the adjusting member 9 is movable relative to the body 10. In analternate embodiment, the fixing feature 12 is configured such that theadjusting member 12 is not movable relative to the body 10 in an axialdirection. In this case, the snap-fit connection is configured withoutplay.

In the first state of the drive mechanism 2, the adjusting member 9 isenabled to rotate freely relative to the body 10. In particular, thefixing feature 12 of the adjusting member 9 and the protrusion 13 of thebody 10 being engaged with each other do not prevent a rotation of theadjusting member 9 relative to the body 10.

The piston rod 3 is configured to be moved relative to the adjustingmember 9 only in a concurrent rotational and axial movement in the firstand in the second state of the drive mechanism 2. For this purpose, theadjusting member 9 comprises a helical thread 14 arranged at its innersurface. The helical thread 14 is a part-thread comprising only parts ofa helical thread. Further, the piston rod 3 comprises a thread 15arranged at its outer surface. The helical thread 14 of the adjustingmember 9 is engaged with the thread 15 of the piston rod 3 in the firstand the second state of the drive mechanism 2.

Accordingly, the adjusting member 9 and the piston rod 3 are threadedlyengaged. Therefore, by rotating the adjusting member 9, e.g. during anassembly of the drive mechanism 2, the piston rod 3 is driven axially ina distal direction 4. In particular, the adjusting member 9 is rotatedduring the assembly process of the drive mechanism 2 until the pistonrod 3 is moved in the distal direction 4 so far that the piston rod 3abuts the bung 7. Thereby, the drive mechanism 2 is transferred to itssecond state. The distance between the piston rod 3 and the bung 7 isnow precisely determined, i.e. the distance equals zero.

FIG. 4 shows an engagement of an external member 17 with the adjustingmember 9.

The adjusting member 9 further comprises a controlling feature 16. Thecontrolling feature 16 is configured to engage with the external member17 in the first state of the drive mechanism 2. For example, theexternal member 17 is an external driving gear which may be part of anassembly machine.

The controlling feature 16 is configured to transfer a rotation of theexternal member 17 into a rotation of the adjusting member 9 relative tothe body 10 in the first state of the drive mechanism 2. In particular,the controlling feature 16 comprises teeth 18 arranged at a periphery ofthe adjusting member 9. In particular, the outer circumference of theadjusting member 9 is formed as a toothed gear.

FIG. 5 shows a part of the drug delivery device 1 in a perspective viewwith some of the elements of the drug delivery device 1 shown partiallytransparent. The body 10 comprises an opening 19 that is arranged at theperiphery of the body 10. The opening 19 is formed such that theexternal member 17 is movable partially through the opening 19 into thebody 10 such that the external member 17 can engage with the controllingfeature 16 of the adjusting member 9. The opening 19 formed in the body10 comprises a slot. Further, a similar opening 20 is formed in thehousing 11 of the drug delivery device 1. In the first state of thedrive mechanism 2, the openings 19, 20 of the body 10 and of the housing11 are arranged such that they overlap each other.

FIG. 6 shows a cross-sectional view of the drive mechanism 2 in itssecond state. The drive mechanism 2 further comprises a rotationpreventing member 21. In the first state of the drive mechanism 2, therotation preventing member 21 is not engaged with other elements of thedrive mechanism 2. In the second state of the drive mechanism 2, therotation preventing member 21 is engaged with the adjusting member 9. Inparticular, the rotation preventing member 21 is engaged with thecontrolling feature 16 of the adjusting member 9. The rotationpreventing member 21 comprises teeth 22 that engage with the teeth 18 ofthe controlling feature 16. Due to this engagement, a further rotationof the adjusting member 9 relative to the body 10 is prevented.

Further, the rotation preventing member 21 engages with the body 10 ofthe drug delivery device 1. This engagement may be a snap-fitengagement. The rotation preventing member 21 comprises snap-fitfeatures 23 that engage with the opening 19 defined in the body 10. Thesnap-fit features 23 which interact with the body 10 are configured suchthat the rotation preventing member 21 cannot be removed from the body10 once it is inserted into the opening 19 without damaging the drugdelivery device 1.

Once the rotation preventing member 21 is engaged with the body 10, therotation preventing member 21 cannot be moved relative to the body 10.As the rotation preventing member 21 is simultaneously engaged with thecontrolling feature 16, the adjusting member 9 can also not be movedrelative to the body 10.

The adjusting member 9 must rest in one of a number of discretepositions defined by the meshing of the teeth 18 of the controllingfeature 16 with the teeth 22 of the rotation preventing member 21.Accordingly, there is a maximum accuracy that can be achieved with thismethod, defined by the number of teeth 18 of the controlling feature 16.

In the following, the assembly process of the drug delivery device 1 isdiscussed. In the first state of the drive mechanism 2, the adjustingmember 9 is engaged to the body 10 by an engagement of the fixingfeature 12 to the body 10 such that the adjusting member 9 is axiallyconstrained and free to rotate relative to the body 10. The body 10, thedrive member, the piston rod 3 and the cartridge holder 5 are alreadyfully assembled in the first state of the drive mechanism 2. The firststate of the drive mechanism 2 may be defined as a state wherein theadjusting member 9 is rotatable relative to the body 10 of the drugdelivery device 1. Further, in the first state, the distal end of thepiston rod 3 is arranged at a not well-defined distance to the bung 7 ofthe cartridge 6. This distance may vary from one drug delivery device 1to another.

Then, the external member 17 is inserted into the openings 19, 20 of thehousing 11 and the body 10. The external member 17 engages with thecontrolling feature 16 of the adjusting member 9. The external member 17is driven rotationally, e.g. by an external motor. The external motor isprovided with some means for detecting the driving torque beingtransmitted, e.g. a torque cell and some means for detecting how far ithas rotated, e.g. a rotary encoder. Alternatively, the external motormay comprise a slip clutch that is designed to slip once a preset torquehas been reached.

The external member 17 being rotated by the external motor causes theadjusting member 9 to rotate. The direction of rotation is chosen suchthat the piston rod 3 is forced to advance axially in the distaldirection 4 towards the bung 7 by the threaded engagement of the pistonrod 3 and the adjusting member 9. As soon as the bearing 8 of the pistonrod 3 contacts the bung 7, an axial load is generated in the piston rod3 which exerts a force on the adjusting member 9 in the proximaldirection 24. This force moves the adjusting member 9 in the proximaldirection 24 into contact with the body 10.

In particular, the adjusting member 9 comprises a first contact surface25. The first contact surface 25 is a flat surface that is perpendicularto a longitudinal axis 26 of the drive mechanism 2. Further, the body 10also comprises a second contact surface 27 being perpendicular to thelongitudinal axis 26 of the drive mechanism 2. When the adjusting member9 is moved in the proximal direction 24 into contact with the body 10,the first contact surface 25 of the adjusting member 9 abuts the secondcontact surface 27 of the body 10. This abutment causes a friction whichimpedes a further rotation of the adjusting member 9 relative to thebody 10, thereby increasing the torque required to rotate the adjustingmember 9 relative to the body 10.

The external motor continues to rotate until the torque reaches apredetermined level which indicates that the desired compressive loadhas been applied to bung 7. Accordingly, the external member 17 can nowbe removed. If a clutch is used, the external member 17 is simplywithdrawn once the clutch begins to slip.

As the desired compressive load is now applied to the bung 7 by thebearing 8 of the piston rod 3, the priming process is complete. Inparticular, the distance between the piston rod 3 and the bung 7 is nowwell-defined.

At this point the rotation preventing member 21 is inserted into theopening 19 of the body 10. The rotation preventing member 21 engageswith the body 10 and with the adjusting member 9, thereby preventing anyfurther rotation of the adjusting member 9 relative to the body 10.

Accordingly, the drive mechanism 2 is now in its second state. Thesecond state of the drive mechanism 2 is defined by the adjusting member9 being prevented from rotating relative to the body 10. In the secondstate of the drive mechanism 2, the distance between the piston rod 3and the bung 7 is well-defined.

Even if the axial load in the piston rod 3 reduces during storage orusage of the drug delivery device 1, the adjusting member 9 is nowprevented from being rotated relative to the body 10 due to itsengagement with the rotation preventing member 21.

Further, the outer surface of the rotation preventing member 21 isdesigned to sit flush with the housing 11. Accordingly, the rotationpreventing member 21 closes the opening 20 of the housing 11 and forms asmooth surface of the housing 11.

FIG. 7 shows the adjusting member 9 being engaged to the body 10according to a second embodiment. According to the second embodiment,the adjusting member 9 also comprises the first contact surface 25 whichabuts the corresponding second contact surface 27 of the body 10 in thesecond state of the drive mechanism 2. Thereby, a rotation of theadjusting member 9 relative to the body 10 is prevented.

In the second embodiment, the first contact surface 25 of the adjustingmember 9 is shaped such that the friction of the frictional engagementis increased. Further, the second contact surface 27 of the body 10 isalso shaped to increase the friction of the frictional engagement. Inparticular, during operation of the drug delivery device 1, a rotationof the adjusting member 9 relative to the body 10 is prevented due to africtional engagement between the first and the second contact surface25, 27.

In particular, the first contact surface 25 of the adjusting member 9and the second contact surface 27 of the body 10 comprise faces 28 whichare arranged relative to the longitudinal axis 26 of the drive mechanism2 in a non-perpendicular angle. In particular, the first and the secondcontact surface 25, 27 comprise faces 28 which are arranged such thatthe surface normal of the faces 28 and the longitudinal axis 26 of thedrive mechanism 2 form an angle in the range of 20° to 70°.

Accordingly, for a given axial load being transferred from the pistonrod 3 to the adjusting member 9, the contact forces are increasedcompared to the contact forces which will occur between parallel contactsurfaces.

In the embodiment shown in FIG. 7, each of the first and the secondcontact surface 25, 27 comprises two faces 28 arranged at anon-perpendicular angle relative to the longitudinal axis 26 of thedrive mechanism 2. However, in alternate embodiments any number ofnon-perpendicular faces 28 may be present. The angle of the faces 28 ischosen to provide the best compromise between allowing the adjustingmember 9 to rotate during the first state of the drive mechanism 2, butnot in the second state of the drive mechanism 2.

Additionally, the rotation preventing member 21 may be inserted into theopening 19 of the body 10 in the second state of the drive mechanism 2.If the rotation preventing member 21 is inserted into the opening 19 ofthe body 10 in the second state of the drive mechanism 2 according tothe second embodiment, the rotation preventing member 21 engages withthe adjusting member 9. According to the second embodiment, theinsertion of the rotation preventing member 21 is optional as a rotationof the adjusting member 9 relative to the body 10 is also prevented bythe frictional engagement of the first contact surface 25 of theadjusting member 9 and the second contact surface 27 of the body 10.Accordingly, the rotation preventing member 21 may provide an additionalprevention of the rotation of the adjusting member 9 relative to thebody 10. Further, the rotation preventing member 21 closing the opening20 of the housing 11 provides for a smooth outer surface of the drugdelivery device 1.

FIG. 8 shows the adjusting member 9 according to a third embodiment. Theadjusting member 9 is identical to the adjusting member 9 according tothe first embodiment except that the first contact surface 25 of theadjusting member 9 comprises locking features 29. The locking features29 are configured to engage with the body 10 when the first contactsurface 25 abuts the body 10 in the second state of the drive mechanism2. Thereby, the locking features 29 prevent the adjusting member 9 fromrotating relative to the body 10.

The locking features 29 comprise ramp features. Further, the secondcontact surface 27 of the body 10 comprises corresponding lockingfeatures (not shown), e.g. identical ramp features. An engagement of thelocking features 29 of the adjusting member 9 with the locking featuresof the body 10 results in rotationally locking the adjusting member 9relative to the body 10.

The assembly of the drug delivery device 1 according to the thirdembodiment is similar to the assembly described with respect to thefirst embodiment. In the first state of the drive mechanism 2, thepiston rod 3 is arranged at a not well-defined distance away from thebung 7 due to mechanical tolerances. Then the external member 17 engageswith the adjusting member 9 and causes the adjusting member 9 to rotaterelative to the body 10, thereby the piston rod 3 is forced to be movedconcurrently rotational and axial in the distal direction 4 relative tothe body 10.

As soon as the bearing 8 of the piston rod 3 contacts the bung 7, anaxial load is generated by the piston rod 3 which will cause theadjusting member 9 to move into abutment with the body 10. This willcause the adjusting member 9 to alternately climb up and then drop downthe ramp features of the body 10 as it is rotated. This is also thereason for the small amount of axial play allowed between the adjustingmember 9 and the body 10 by the fixing feature 12 being engaged to thebody 10. The external member 17 continues to rotate until the torquerequired to rotate the adjusting member 9 has reached a predeterminedlevel indicating that the desired compressive load has been applied tothe bung 7.

If a torque cell and an encoder are used, at this point the externalmember 17 will rotate to the nearest position at which the lockingfeatures 29 of the adjusting member 9 are fully interlocked with thelocking features of the body 10. When the external member 17 is removed,the locking features 29 prevent any further rotation of the adjustingmember 9 relative to the body 10. If a clutch is used instead, then theexternal member 17 is simply withdrawn once the clutch begins to slip,the axial load in the piston rod 3 will then force the adjusting member9 to rotate slightly until the locking features 29 of the adjustingmember 9 are fully engaged with the locking features of the body 10.

The size of the locking features 29 determines the angular resolutionand hence the accuracy that is achievable with this embodiment.

The rotation preventing member 21 may additionally be used to provide anextra securing against a rotation of the adjusting member 9 and toprovide for a smooth outer surface of the drug delivery device 1. Thenumber of teeth 18 of the controlling feature 16 of the adjusting member9 is related to the number of locking features 29 in such a way that therotation preventing member 21 will always align correctly to thecontrolling feature 16 when the locking features 29 of the adjustingmember 9 are fully interlocked with the locking features of the body 10.In this embodiment, the rotation preventing member 21 can additionallycomprise a feature which prevents the adjusting member 9 from movingaxially relative to the body 10 in the second state of the drivemechanism 2 by removing the axial play between the adjusting member 9and to the body 10.

FIG. 9 shows the drive mechanism 2 according to a fourth embodiment. Thefirst contact surface 25 of the adjusting member 9 is engaged to thesecond contact surface 27 of the body 10 by an adhesive 30 in the secondstate of the drive mechanism 2. Each of the first and the second contactsurface 25, 27 is flat and arranged perpendicular to the longitudinalaxis 26 of the drive mechanism 2. This results in the advantage ofallowing a high resolution in the angular position of the adjustingmember 9 relative to the body 10 which translates to a precise axialload on the bung 7.

Once the first contact surface 25 of the adjusting member 9 and thesecond contact surface 27 of the body 10 abut each other, they may becoupled by the adhesive 30. Additionally or alternatively, the adhesive30 may be activated using ultraviolet light, ultrasonically or by usingradio frequency energy.

The first and the second contact surface 25, 27 are designed to form astrong engagement without allowing excess adhesive to escape into otherparts of the drive mechanism 2.

In this embodiment, the rotation prevention member 21 is not required toprevent a rotation of the adjusting member 9 relative to the body 10.Nevertheless, the rotation preventing member 21 may be used to provideadditional rotation preventing security and to provide a smooth outersurface of the drug delivery device 1.

FIG. 10 shows the drive mechanism 2 according to a fifth embodiment.

In FIG. 10, the adjusting member 9 is welded to the body 10.Accordingly, in the second state of the drive mechanism 2, due to thewelded engagement of the adjusting member 9 and the body 10, a rotationof the adjusting member 9 relative to the body 10 is prevented. Duringthe assembly of the drug delivery device 1, the external member 17engages the adjusting member 9 and rotates the adjusting member 9 untilthe torque required to rotate the external member 17 reaches apredetermined amount. Then, a laser beam 31 is directed to the first andthe second contact surface 25, 27 of the adjusting member 9 and the body10 with the external member 17 still engaged to the adjusting member 9.The laser beam 31 welds the first and the second contact surface 25, 27together. Once the welded connection between the first and the secondcontact surface 25, 27 is cooled the external member 17 can be removed.

This embodiment also allows for flat contact surfaces 25, 27 of theadjusting member 9 and the body 10 resulting in allowing a highresolution in the angular position of the adjusting member 9 relative tothe body 10 which translate to a precise axial load on the bung 7.

Again, a rotation preventing member 21 is optional, providing theadvantage of an additional rotation preventing security and a smoothouter surface of the drug delivery device 1.

FIG. 11 shows the drug delivery device 1 according to a sixthembodiment. According to this embodiment, the rotation preventing member21 is used to prevent a rotation of the adjusting member 9 relative tothe body 10 in the second state of the drive mechanism 2. In the sixthembodiment, the rotation preventing member 21 comprises a metal staple.

The assembly process of the drug delivery device 1 according to thesixth embodiment is similar to the assembly process discussed withrespect to the first embodiment. It differs from the assembly process ofthe first embodiment only in that the rotation preventing member 21 isengaged to the adjusting member 9 while the external member 17 is stillengaged with the controlling feature 16, as shown in FIG. 11.

FIGS. 12 and 13 show the drug delivery device 1 wherein the rotationpreventing member 21 is engaged with the adjusting member 9. Therotation preventing member 21 is pierced through the body 10 and theadjusting member 9 thereby preventing a further movement of theadjusting member 9 relative to the body 10.

A variation of shape of the rotation preventing member 21 is possible.FIGS. 11 and 12 show the rotation preventing member 21 comprising ametal staple comprising two prongs 31. The staple may alternativelycomprise one, three or more prongs 31. The outer surface of the rotationpreventing member 21 sits flush with the housing 11 in the second stateof the drive mechanism 2, as shown in FIG. 13. Alternatively, the outersurface of the rotation preventing member 21 may be recessed inwards. Inan alternate embodiment of the rotation preventing member 21, therotation preventing member 21 may comprise a flap of metal (not shown)which can be folded over to cover up the opening 20 in the housing 11once the external member 17 is removed.

In this embodiment the first and the second contact surfaces 25, 27 ofthe adjusting member 9 and respectively of the body 10 are flat,providing the advantages of a high resolution and a precise axial loadon the bung 7. The rotation preventing member 21 as shown in FIG. 1 isoptional in this embodiment and may additionally provide for extralocking security and a smooth outer surface of the drug delivery device1.

FIG. 14 shows the drive mechanism 2 according to a seventh embodiment.In the seventh embodiment, a sleeve member 32 is engaged to theadjusting member 9 in the second state of the drive mechanism 2. Thesleeve member 32 may comprise a lead screw sleeve. The sleeve member 32comprises a first locking member 33 at its distal end. Further, theadjusting member 9 comprises a corresponding second locking member 34.In the second state of the drive mechanism 2, the first locking member33 of the sleeve member 32 is engaged to the second locking member 34 ofthe adjusting member 9.

The first locking member 33 of the sleeve member 32 comprises aprojection, e.g. a clicker arm. The second locking member 34 of theadjusting member 9 comprises teeth arranged at an inner surface of theadjusting member 9, e.g. ratchet teeth. The first and the second lockingmember 33, 34 are configured such that they permit a rotation of thesleeve member 32 in a first rotational direction and prevent a rotationof the sleeve member 32 in the second rotational direction relative tothe adjusting member 9 when engaged to each other.

An engagement of the first and the second locking member 33, 34 mayresult in an uneven torque profile when the adjusting member 9 isrotated relative to the sleeve member 32 and the body 10. This makes itdifficult to accurately determine when the contact between the bearing 8and the bung 7 is achieved. To avoid this, the adjusting member 9 may berotated before the second locking member of the adjusting member 9 isengaged with the first locking member of the sleeve member 32.

Accordingly, the sleeve member 32 is positioned in a proximal positionin a distance to the adjusting member 9 in the first state of the drivemechanism 2, as shown in FIG. 15. The adjusting member 9 is then engagedwith the external member 17 rotating the adjusting member 9 and therebymoving the piston rod 3 in the distal direction 4. When the bearing 8contacts the bung 7, the axial load generated in the piston rod 3 willcause the adjusting member 9 to move into contact with the body 10. Theexternal member 17 continues to rotate until the torque has reached thepredetermined level indicating that the desired compressive load hasbeen applied to the bung 7. The adjusting member 9 can now be locked inits position relative to the body 10 using any of the techniquesdescribed with respect to the first to sixth embodiments.

In the next assembly step, the sleeve member 32 is moved axially in adistal direction 4 such that the first locking member 33 of the sleevemember 32 engages with the second locking member 34 of the adjustingmember 9 as shown in FIG. 16.

If the sleeve member 32 is not present in the first state, an assemblytool may be configured to prevent a purely rotational movement of thepiston rod 3 relative to the body 10 when the adjusting member 9 isrotated.

The drive mechanism 2 according to a seventh embodiment furthercomprises a dial screw 41. During dispense, the dial screw 41 moveshelically and the sleeve member 32 moves rotationally. The sleeve member32 is rotationally constrained to the piston rod 3. The piston rod 3 isthreadedly engaged to the adjusting member 9. Rotating the sleeve member32 therefore causes the piston rod 3 to travel helically duringdispense.

FIG. 17 shows the drive mechanism 2 when an alternative assembly tool(not shown) is used. The alternative assembly tool drives the piston rod3 axially in the distal direction 4, resulting in a rotation of theadjusting member 9 relative to the piston rod 3 and, thus, relative tothe body 10. The use of the alternative assembly tool can be combinedwith any of the first to seventh embodiments of the drive mechanism 2.

FIGS. 18 to 20 show the assembly process of the drug delivery device 1according to an eighth embodiment.

In the eighth embodiment, the adjusting member 9 is enabled to rotatefreely relative to the body 10 when a load is applied by the piston rod3 on the adjusting member 9. The adjusting members 9 according to thesecond and the third embodiment are self locking, i.e. the adjustingmembers 9 according to the second and the third embodiment are preventedfrom rotating relative to the body 10 when a load is applied by thepiston rod 3 on the adjusting member 9. Further, the adjusting members 9according to the first, the fourth, the fifth, the sixth and the seventhembodiment may be configured either to be enabled to rotate freelyrelative to the body 10 when a load is applied by the piston rod 3 onthe adjusting member 9 or may be configured to be prevented fromrotating relative to the body 10 when a load is applied by the pistonrod 3 on the adjusting member 9.

FIG. 18 shows the drug delivery device 1 according to the eighthembodiment in a first stage of the assembly process. The body 10, thepiston rod 3, the adjusting member 9 and the sleeve member 32 areassembled together and form a sub-assembly. Moreover, a last dose memberand a drive member may also be assembled to the sub-assembly. The pistonrod 3 is threadedly engaged with the adjusting member 9. In the firststage, the piston rod 3 is positioned such that the piston rod 3 makescontact with the bung 7 of the cartridge 6 in a later assembly stage.

The sub-assembly is then arranged inside the housing 11 which is engagedwith the cartridge holder 5 containing the cartridge 6 with the bung 7.

The adjusting member 9 is configured such that it is enabled to rotaterelative to the body 10 even if the piston rod 3 applies a load onto theadjusting member 9 in the proximal direction 24.

FIG. 19 shows a second stage of the assembly process of the drugdelivery device 1 according to the eighth embodiment. The sub-assemblyis moved axially in the distal direction 4 until the bearing 8 of thepiston rod 3 abuts the bung 7.

Thereby, the third stage of the assembly process is initiated. FIG. 20shows the drug delivery device 1 in the third stage of the assemblyprocess.

In the third stage of the assembly process, a further movement of thepiston rod 3 in the distal direction 4 is prevented by the abutment ofthe piston rod 3 and the bung 7. The drive member causes the piston rod3 to rotate, i.e. the drive member is fixed in rotation relative to thebody 10 and is being pushed in axially in the distal direction 4.Further, the drive member is threaded to the piston rod 3, so it causesthe piston rod 3 to rotate. Further, the rotation of the piston rod 3causes the adjusting member 9 to rotate relative to the body 10.

In the first to seventh embodiments, the adjusting member 9 may beconfigured to self-lock when an axial load is applied to the adjustingmember 9 by the piston rod 3. However, in the eighth embodiment, theadjusting member 9 is required to rotate when a load is applied to thepiston rod 3, therefore it is not possible to rely on friction againstthe body 10 to lock the adjusting member 9. The locking techniquesdiscussed above which do not rely on friction between the adjustingmember 9 and the body 10 may also be applied to the eighth embodiment,e.g. locking by adhesive or by welding.

FIG. 21 shows a cross-sectional perspective view of the body 10according to a ninth embodiment. FIG. 22 shows a perspective view of theadjusting member 9 according to the ninth embodiment. The ninthembodiment differs from the eighth embodiment only in respect to thefixing of the adjusting member 9 in the last step of the assemblyprocess.

The body 10 comprises a first engagement feature 35 arranged at itsinner surface. The first engagement feature 35 comprises a locking arm.The first engagement feature 35 comprises teeth. The first engagementfeature 35 of the body 10 is not engaged with the adjusting member 9 inthe first state of the drive mechanism 2.

Moreover, the adjusting member 9 comprises second engagement feature 36.The second engagement feature 36 comprises teeth arranged at theperiphery of the adjusting member 9.

FIGS. 23 and 24 show the drug delivery device 1 according to the ninthembodiment in the first state of the drive mechanism 2.

In the ninth embodiment, the body 10 is configured such that the body 10can be rotated relative to the housing 11.

After the adjustment of the axial position of the piston rod 3 has beencompleted, the body 10 is rotated relative to the housing 11. The body10 has a non-circular outer diameter 37. The housing 11 has anon-circular inner surface 38 comprising a ramp member 39. Thereby, dueto the rotation of the body 10 relative to the housing 11, the firstengagement feature 35 of the body 10 is forced inwards by the rampmember 39 of the housing 11. In the second state of the drive mechanism2, the first engagement feature 35 of the body 10 engages with thesecond engagement feature 36 of the adjusting member 9.

When the first and the second engagement feature 35, 36 are engaged witheach other a further rotation of the adjusting member 9 relative to thebody 10 is prevented. The adjusting member 9 must rest in one of anumber of discrete positions defined by the meshing of the teeth on theadjusting member 9 with the teeth on the first engagement feature 35 forthe first and the second engagement feature 35, 36 to engage with eachother. Accordingly, there is a maximum accuracy that can be achieved bythis method, defined by the number of teeth.

FIGS. 25 and 26 show the drug delivery device 1 according to the ninthembodiment in the second state of the drive mechanism 2.

FIG. 27 shows the adjusting member 9 according to a tenth embodiment ina perspective view.

FIG. 28 shows the drug delivery device 1 according to the tenthembodiment in the second state of the drive mechanism 2.

In the tenth embodiment, the second engagement feature 36 comprises afragile surface 40 that is configured to be crushed when the firstengagement feature 35 of the body 10 engages with the second engagementfeature 36. The fragile surface 40 is formed by thin rings that arearranged around the circumference of the adjusting member 9. When thefirst engagement feature 35 of the body 10 is forced inwards by the rampmember 39 of the housing 11, the first engagement feature 35 crushes thefragile surface 40 and locks the adjusting member 9 in its rotationalposition relative to the body 10. This allows the adjusting member 9 tobe positioned at any rotary position not limited by the need for thefirst engagement feature 35 to engage with corresponding teeth on theadjusting member 9.

According to an eleventh embodiment, the amount of adjustment in theaxial position of the piston rod 3 is determined by a measurement of thepositions of the bearing 8 and the bung 7. The sub-assembly is fullyassembled as described with respect to the eighth embodiment and theposition of the bearing 8 is measured relative to a stop face on thebody 10. The cartridge 6 is assembled into the housing 11 and theposition of the bung 7 is measured relative to the stop face. A preloadforce can be applied to the bung 7 at this stage if desired.

With the positions of the bung 7 and the bearing 8 known, the adjustingmember 9 can be rotated through a known angle to eliminate the gapbetween the bung 7 and the bearing 8. A benefit of this concept is thatit does not rely on measuring a very small torque to accurately positionthe piston rod 3. Another benefit is that it may also be possible torotate the adjusting member 9 by inserting an alternative embodiment ofthe external member 17 axially into the body 10, rather than via anexternal member 17 inserted from the side. This would slightly simplifythe assembly process by allowing all assembly head movements to bealigned with the longitudinal axis 26 of the drive mechanism 2.

After the assembly is completed, the adjusting member 9 is locked in itsposition using one of the first to tenth embodiment described above.

The invention claimed is:
 1. A drive mechanism for a drug deliverydevice, the drive mechanism comprising: a piston rod; an adjustingmember; and a rotation preventing member, wherein the drive mechanismhas a first state in which the drive mechanism is operable to perform apriming operation and a second state in which the drive mechanism isoperable to perform a dose setting operation and a dose dispensingoperation, wherein the adjusting member is rotatable relative to a bodyof the drug delivery device in the first state of the drive mechanismand is configured to be prevented from rotating relative to the body inthe second state of the drive mechanism, wherein the adjusting member isconfigured to adjust an axial position of the piston rod in the firststate of the drive mechanism, wherein the piston rod is configured to bemoved in a distal direction when the drive mechanism is operated in itsfirst state, and wherein the piston rod is moveable relative to theadjusting member in the second state of the drive mechanism, wherein theadjusting member is configured to constrain a movement of the piston rodin the second state of the drive mechanism such that the piston rod ispermitted only to carry out a concurrent axial and rotational movementrelative to the adjusting member, and wherein the rotation preventingmember is configured to be engaged with the adjusting member in thesecond state of the drive mechanism, thereby preventing the adjustingmember from rotating relative to the body.
 2. The drive mechanismaccording to claim 1, wherein the adjusting member is configured suchthat rotation of an external member is converted into rotation of theadjusting member.
 3. The drive mechanism according to claim 2, whereinthe adjusting member is configured to be engaged with the externalmember in the first state of the drive mechanism.
 4. The drive mechanismaccording to claim 1, wherein the adjusting member comprises a firstcontact surface, and wherein, in the second state of the drivemechanism, the first contact surface of the adjusting member abuts thebody, thereby preventing the adjusting member from rotating relative tothe body.
 5. The drive mechanism according to claim 4, wherein the firstcontact surface is configured such that a frictional engagement betweenthe first contact surface and the body prevents the adjusting memberfrom rotating relative to the body in the second state of the drivemechanism.
 6. The drive mechanism according to claim 4, wherein, in thesecond state of the drive mechanism, a force in a proximal direction isexerted onto the adjusting member thereby bringing the first contactsurface of the adjustment member in abutment with the body.
 7. The drivemechanism according to claim 4, wherein the first contact surfacecomprises locking features that are configured to engage with the bodywhen the first contact surface abuts the body in the second state of thedrive mechanism, thereby preventing the adjusting member from rotatingrelative to the body.
 8. The drive mechanism according to claim 1,wherein an adhesive prevents the adjusting member from rotating relativeto the body in the second state of the drive mechanism.
 9. The drivemechanism according to claim 1, wherein the adjusting member comprises afixing feature, and wherein the fixing feature is configured to engagewith the body of the drug delivery device such that the adjusting memberis either moveable in an axial direction relative to the body only by asmall predetermined distance or prevented from moving in the axialdirection relative to the body.
 10. The drive mechanism according toclaim 1, wherein the adjusting member is welded to the body in thesecond state of the drive mechanism.
 11. A drive mechanism for a drugdelivery device, the drive mechanism comprising: a piston rod; and anadjusting member, wherein the adjusting member is rotatable relative toa body of the drug delivery device in a first state of the drivemechanism and is configured to be prevented from rotating relative tothe body in a second state of the drive mechanism, wherein the drivemechanism has a first state in which the drive mechanism is operable toperform a priming operation and a second state in which the drivemechanism is operable to perform a dose setting operation and a dosedispensing operation, wherein the adjusting member is configured toadjust an axial position of the piston rod in the first state of thedrive mechanism, wherein the piston rod is configured to be moved in adistal direction when the drive mechanism is operated in its firststate, and wherein the piston rod is moveable relative to the adjustingmember in the second state of the drive mechanism, wherein the adjustingmember is configured to constrain a movement of the piston rod in thesecond state of the drive mechanism such that the piston rod ispermitted only to carry out a concurrent axial and rotational movementrelative to the adjusting member, wherein the adjusting member comprisesa first contact surface, and wherein, in the second state of the drivemechanism, the first contact surface abuts the body, thereby preventingthe adjusting member from rotating relative to the body.
 12. A drivemechanism for a drug delivery device, the drive mechanism comprising: apiston rod; and an adjusting member, wherein the adjusting member isrotatable relative to a body of the drug delivery device in a firststate of the drive mechanism and is configured to be prevented fromrotating relative to the body in a second state of the drive mechanism,wherein the adjusting member is configured to adjust an axial positionof the piston rod in the first state of the drive mechanism, wherein thepiston rod is configured to be moved in a distal direction when thedrive mechanism is operated in its first state, and wherein the pistonrod is moveable relative to the adjusting member in the second state ofthe drive mechanism, and wherein an adhesive prevents the adjustingmember from rotating relative to the body in the second state of thedrive mechanism or the adjusting member is welded to the body in thesecond state of the drive mechanism.
 13. A drive mechanism for a drugdelivery device, the drive mechanism comprising: a piston rod; and anadjusting member, wherein the drive mechanism has a first state in whichthe drive mechanism is operable to perform a priming operation and asecond state in which the drive mechanism is operable to perform a dosesetting operation and a dose dispensing operation, wherein the adjustingmember is rotatable relative to a body of the drug delivery device inthe first state of the drive mechanism and is configured to be preventedfrom rotating relative to the body in the second state of the drivemechanism, wherein the adjusting member is configured to adjust an axialposition of the piston rod in the first state of the drive mechanism,wherein the piston rod is configured to be moved in a distal directionwhen the drive mechanism is operated in its first state, and wherein thepiston rod is moveable relative to the adjusting member in the secondstate of the drive mechanism, wherein the adjusting member is configuredto constrain a movement of the piston rod in the second state of thedrive mechanism such that the piston rod is permitted only to carry outa concurrent axial and rotational movement relative to the adjustingmember, wherein the adjusting member comprises a fixing feature, andwherein the fixing feature is configured to engage with the body of thedrug delivery device such that the adjusting member is either moveablein an axial direction relative to the body only by a small predetermineddistance or prevented from moving in the axial direction relative to thebody.